Diagnosis of cerebral amyloid angiopathy by enzyme-linked immunosorbent assay of cystatin C in cerebrospinal fluid.

Shimode, Koichi; Fujihara, Shigeyoshi; Nakamura, Morihiko; Kobayashi, Shotai; Takemoto, Tsunematsu

doi:10.1161/01.str.22.7.860

Cited by 34 publications

(16 citation statements)

References 20 publications

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“…The concentration of cystatin C in the CSF of HCHWA-I patients is lower compared with normal controls (20). There are several reports of patients with cerebral hemorrhage related to CAA with low concentration of cystatin C in the CSF (21)(22)(23). Immunohistochemical examination of brain tissue obtained from two of these patients confirmed the diagnosis of CAA and identified co-deposition of cystatin C and amyloid ␤-protein.…”

mentioning

confidence: 74%

Instability of the Amyloidogenic Cystatin C Variant of Hereditary Cerebral Hemorrhage with Amyloidosis, Icelandic Type

Wei

Berman

Castaño

et al. 1998

Journal of Biological Chemistry

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A cystatin C variant with L68Q substitution and a truncation of 10 NH 2 -terminal residues is the major constituent of the amyloid deposited in the cerebral vasculature of patients with the Icelandic form of hereditary cerebral hemorrhage with amyloidosis (HCHWA-I). Variant and wild type cystatin C production, processing, secretion, and clearance were studied in human cell lines stably overexpressing the cystatin C genes. Immunoblot and mass spectrometry analyses demonstrated monomeric cystatin C in cell homogenates and culture media. While cystatin C formed concentration-dependent dimers, the HCHWA-I variant dimerized at lower concentrations than the wild type protein. Amino-terminal sequence analysis revealed that the variant and normal proteins produced and secreted are the full-length cystatin C.Pulse-chase experiments demonstrated similar levels of normal and variant cystatin C production and secretion. However, the secreted variant cystatin C exhibited an increased susceptibility to a serine protease in conditioned media and in human cerebrospinal fluid, explaining its depletion from the cerebrospinal fluid of HCHWA-I patients. Thus, the amino acid substitution may induce unstable cystatin C with intact inhibitory activity and predisposition to self-aggregation and amyloid fibril formation.

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mentioning

confidence: 74%

Instability of the Amyloidogenic Cystatin C Variant of Hereditary Cerebral Hemorrhage with Amyloidosis, Icelandic Type

Wei

Berman

Castaño

et al. 1998

Journal of Biological Chemistry

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“…Among these subjects, 8 patients were identified with abdominal aortic dilatation as defined with periumbilical aorta diameter larger than 2.5 cm. Serum samples from all patients were collected and used for cystatin C ELISA as described elsewhere (17)(18)(19). Briefly, 96-well immunosorb plates (NUNC Co., Naperville, Illinois, USA) were coated with cystatin C polyclonal IgG (10 µg/mL; Cortex Biochem) in NaHCO 3 (pH 8.2) overnight at 4°C.…”

Section: Figurementioning

confidence: 99%

“…We measured the serum cystatin C levels in these patients using a cystatin C ELISA. This method has been previously used to quantify cystatin C levels in human gingiva (17), cerebrospinal fluid (18), and normal serum (19). The serum cystatin C levels were quantitated against a recombinant cystatin C standard.…”

Section: Figurementioning

confidence: 99%

“…Cystatins D, S, and SA are primarily expressed in salivary glands, cystatin C is expressed in virtually all organs of the body. Owing to its high concentration in biologic fluids, cystatin C is probably one of the most important extracellular inhibitors of cysteine proteases (15)(16)(17)(18)(19). Aside from a rare mutation in cystatin C that leads to its precipitation as amyloid in cerebral blood vessels and causes cerebral hemorrhage (20), no evidence thus far has implicated cystatin C in disease.…”

Section: Introductionmentioning

confidence: 99%

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Cystatin C deficiency in human atherosclerosis and aortic aneurysms

Shi

Sukhova

Grubb³

et al. 1999

J. Clin. Invest.

423

400

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“…Plasma CST3 levels were quantified using a latex immunoagglutination assay system (Toshiba 200FR analyzer; Toshiba). CST3 levels in the conditioned culture medium were determined using an ELISA [16]. The results are presented relative to normalized luminescence derived from the cytomegalovirus-promoter-driven Renilla luciferase vector using a luciferase reporter assay system (Promega Corp.).…”

Section: Methodsmentioning

confidence: 99%

Contribution of Cystatin C Gene Polymorphisms to Cerebral White Matter Lesions

Mitaki

Nagai²,

Sheikh³

et al. 2011

Cerebrovasc Dis

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Background: Vascular remodeling plays an important role in the development of arteriosclerosis and any of the resulting white matter lesions in the brain. An imbalance between cysteine proteases and the cysteine protease inhibitor cystatin C (CST3) may exacerbate vascular remodeling through degradation of extracellular matrix proteins. Therefore, we evaluated the association between functional polymorphisms in the CST3 gene and the development of cerebral white matter lesions. Methods: In a total of 2,676 participants, 3 CST3 genepolymorphisms were genotyped in 92 cases with severe deep white matter hyperintensity (DWMH), and 184 subjects were randomly selected age- and sex-matched controls without any signs of DWMH. The genetic effects of these polymorphisms on DWMH and plasma CST3 levels were examined. CST3 expression vectors were transfected into an astrocytoma cell line and the expression level of CST3 mRNA was analyzed by quantitative RT-PCR. Intracellular and secreted levels of CST3 in the cell culture were quantified by Western blot and ELISA, respectively. Results: A significant association was found between one CST3 gene haplotype and DWMH (p = 0.002). This haplotype was also associated with lower plasma CST3 levels (p = 0.01). An in vitro transfection study revealed that the +148A allele, which is included in the risk haplotype, significantly reduced the secretion and increased the intracellular accumulation of CST3; however, it had no effect on the mRNA expression. Conclusions: Our study shows that polymorphisms in the CST3 gene are significantly associated with the likelihood of DWMH. Substitution of A for G at +148 of the CST3 gene decreased the extracellular availability of CST3 in vitro, which might result in the activation of protease activity.

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Diagnosis of cerebral amyloid angiopathy by enzyme-linked immunosorbent assay of cystatin C in cerebrospinal fluid.

Cited by 34 publications

References 20 publications

Instability of the Amyloidogenic Cystatin C Variant of Hereditary Cerebral Hemorrhage with Amyloidosis, Icelandic Type

Instability of the Amyloidogenic Cystatin C Variant of Hereditary Cerebral Hemorrhage with Amyloidosis, Icelandic Type

Cystatin C deficiency in human atherosclerosis and aortic aneurysms

Contribution of Cystatin C Gene Polymorphisms to Cerebral White Matter Lesions

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